Zinc-Dependent Suppression of TNF-α Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, IκB Kinase β, and NF-κB

Abstract

Excessive and permanent cytokine production in response to bacterial LPS causes cell and tissue damage, and hence organ failure during sepsis. We have previously demonstrated that zinc treatment prevents LPS-induced TNF-α expression and production in human monocytes by inhibiting cyclic nucleotide phosphodiesterase (PDE) activity and expression, and subsequent elevation of the cyclic nucleotide cGMP. In the present study, we investigated the molecular mechanism by which cGMP signaling affects the LPS-induced signaling cascade to suppress TNF-α transcription and release from monocytes. Zinc-mediated cGMP elevation led to cross activation of protein kinase A. This zinc-induced protein kinase A activation inhibited Raf-1 activity by phosphorylation at serine 259, preventing activation of Raf-1 by phosphorylation of serine 338. By this mechanism, zinc suppressed LPS-induced activation of IκB kinase β (IKKβ) and NF-κB, and subsequent TNF-α production. Our study shows that PDE inhibition by zinc modulates the monocytic immune response by selectively intervening in the Raf-1/IKKβ/NF-κB pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.

Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling

“…This is explained by a concentration-dependent process, in which low zinc doses potentiate cytokine production, while its high concentrations inhibit cytokine secretion [40]. In our experiment, we chose a rather low 30 M concentration of zinc, which did not exhibit any toxicity for HSCs in vitro, and which represented a maximal level of zinc attainable for humans after oral supplementation [41,42]. Zinc at this concentration significantly inhibited ethanol-and acetaldehyde-induced TGF-1 and TNF- production in HSCs.…”

Zinc Signals Are Essential for Lipopolysaccharide-Induced Signal Transduction in Monocytes

“…Zinc cannot only reduce mRNA expression of proinflammatory cytokines in cultured cells (15), it also inhibits LPS-mediated toxicity in mice (16,30). Although the molecular mechanism that leads to the inhibition by high zinc concentrations was found to be based on a modulation of cGMP signaling (17,18), only few data exist regarding the mechanism furthering proinflammatory events. An effect of zinc on the fluidity state of LPS, and hereby the interaction with its receptor, was discussed (31).…”

“…Although low concentrations act synergistically with LPS (19,20), higher ones inhibit the production of these cytokines (15)(16)(17)(18). Zinc cannot only reduce mRNA expression of proinflammatory cytokines in cultured cells (15), it also inhibits LPS-mediated toxicity in mice (16,30).…”

“…Some observations indicated that zinc treatment inhibits the production of these cytokines (15,16). This reduction is mediated by inhibition of cyclic nucleotide phosphodiesterases by relatively high zinc concentrations (17,18). Other reports describe zinc as an activator of proinflammatory cytokine production and that it acts synergistically with LPS if applied simultaneously at substimulatory concentrations (19,20).…”

Zinc in Infection and Inflammation

“…PPAR-α increase leads to the down-regulation of inflammatory cytokines and adhesion molecule [42]. Additionally, zinc acts as an inhibitor of cyclic nucleotide phosphodiesterase (PDE), when PDE is inhibited, cyclic nucleotide cGMP (Cyclic guanosine monophosphate) is elevated leading to the activation of PKA (protein kinase A) and subsequent inhibition of NF-κB [43]. Similarly, zinc can bind to a zinc finger-like motif found on protein kinase C (PKC) and inhibit PMA-mediated PKC translocation to the membrane, when this occurs in mast cells, NF-κB activity is indirectly inhibited [44].…”